Have you ever taken paracetamol? The answer is likely a resounding yes. Perhaps even in the past few days, some of you have relied on this medicine to alleviate minor aches and pains or to reduce a fever. This ubiquitous drug has now become a part of the IMPACTIVE family.
In a recent paper published in the journal ChemSusChem, we accomplished the use of bead-milling technology for the solvent-free synthesis of paracetamol1. This is the first use of such method to perform a reaction in the absence of solvent – it normally operates under wet milling conditions. And not just that. This sustainable mechanochemical synthesis of the drug outperformed traditional solution-based methods, achieving superior yields and improved green chemistry metrics.
“This is an additional proof of concept that mechanochemistry is a real opportunity for APIs synthesis at different scale,” says Evelina Colacino, from the Institute Charles Gerhardt (ICGM) at the University of Montpelier, IMPACTIVE coordinator and one of the authors of the work. They successfully arrive to a final product on a scale of several tens of grams.
Bead-mills use fixed pieces to mill and grind chemicals. They are extensively used in industries such as paint and lacquer manufacturing, mineral grinding, and the processing of chemicals, food, and pharmaceuticals. However, these applications typically involve the use of solvents.
Given the significant increase in paracetamol production in the past few years, and predictions indicating this trend will continue, adopting mechanochemical processes to make its manufacturing more sustainable is highly appealing. One main chemical route to produce this drug is the Hoechst-Celanese. This is a five-step process that relies in a Beckmann rearrangement — a rearrangement of an oxime functional group to substituted amides. And this is the strategy the authors followed to do their mechanomagic.
So basically, the work involved substituting the traditional steps in the Hoechst-Celanese process (the same the industry uses to manufacture paracetamol in solution) with solvent-free steps and comparing both techniques. The metrics favoured the mechanochemical process. The main advantages of mechanochemistry include:
- Better yield. The results clearly favoured mechanochemistry, achieving a production of 7.45 grams in just 75 minutes. While this may seem modest, it represents a significant success for potential scalability.
- Safer reaction conditions. The developed strategy eliminates the need for toxic reagents and operates under mild reaction conditions.
- Greener metrics. This approach aligns with the 12 principles of Green Chemistry.
And there’s more! Bead-mills offer the added advantage of versatility in the mechanochemical context, as they can be used for both batch and continuous synthesis depending on how the mixture of solids is fed.
So we can say this is a successful proof of concept. In fact, it’s more of a double one. Firstly, it demonstrates the synthesis of paracetamol using mechanochemistry with this equipment. Secondly, it shows that this equipment can be adapted to perform dry chemistry instead of wet chemistry and do so very successfully.
“This equipment, which is already available on the market for formulation purposes (among other applications in industry), has now been used for synthesis, meaning the formation of covalent bonds. That’s innovative,” says Evelina Colacino.
There are some aspects to be careful, though, especially when it comes to scalability. For instance, we still miss data from Life Cycle Analysis (LCA), and we have limited information about the thermodynamics at a larger scale.
Part of our work within the IMPACTIVE project is precisely to advance beyond the lab, moving from grams range up to kilograms range. We have several partners taking care of this: DES Solutio in Portugal, the Max Planck Institute in Germany, the CGSI in Italy, and HES-SO in Switzerland, which is an associated partner to the project. They will ensure things also work industrially, which usually means scaling up quantities and smoothing some aspects to ensure efficiency.
- This work was stems from the COST Action CA18112 ‘Mechanochemistry for Sustainable Industry’ (www.mechsustind.eu), where it was started, and finally accomplished during IMPACTIVE. ↩︎
